(−)‐[ 18 F]Flubatine: evaluation in rhesus monkeys and a report of the first fully automated radiosynthesis validated for clinical use

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/101867/1/jlcr3069.pd

Development and implementation of ISAR, a new synthesis platform for radiopharmaceutical production

Abstract Background PET radiopharmaceutical development and the implementation of a production method on a synthesis module is a complex and time-intensive task since new synthesis methods must be adapted to the confines of the synthesis platform in use. Commonly utilized single fluid bus architectures put multiple constraints on synthesis planning and execution, while conventional microfluidic solutions are limited by compatibility at the macro-to-micro interface. In this work we introduce the ISAR synthesis platform and custom-tailored fluid paths leveraging up to 70 individually addressable valves on a chip-based consumable. The ISAR synthesis platform replaces traditional stopcock valve manifolds with a fluidic chip that integrates all fluid paths (tubing) and valves into one consumable and enables channel routing without the single fluid bus constraint. ISAR can scale between the macro- (10 mL), meso- (0.5 mL) and micro- (≤0.05 mL) domain seamlessly, addressing the macro-to-micro interface challenge and enabling custom tailored fluid circuits for a given application. In this paper we demonstrate proof-of-concept by validating a single chip design to address the challenge of synthesizing multiple batches of [13N]NH3 for clinical use throughout the workday. Results ISAR was installed at an academic PET Center and used to manufacture [13N]NH3 in > 96% radiochemical yield. Up to 9 batches were manufactured with a single consumable chip having parallel paths without the need to open the hot-cell. Quality control testing confirmed the ISAR-based [13N]NH3 met existing clinical release specifications, and utility was demonstrated by imaging a rodent with [13N]NH3 produced on ISAR. Conclusions ISAR represents a new paradigm in radiopharmaceutical production. Through a new system architecture, ISAR integrates the principles of microfluidics with the standard volumes and consumables established in PET Centers all over the world. Proof-of-concept has been demonstrated through validation of a chip design for the synthesis of [13N]NH3 suitable for clinical use.https://deepblue.lib.umich.edu/bitstream/2027.42/152186/1/41181_2019_Article_77.pd

Futureproofing [18F]Fludeoxyglucose manufacture at an Academic Medical Center

Abstract Background We recently upgraded our [18F]fludeoxyglucose (FDG) production capabilities with the goal of futureproofing our FDG clinical supply, expanding the number of batches of FDG we can manufacture each day, and improving patient throughput in our nuclear medicine clinic. In this paper we report upgrade of the synthesis modules to the GE FASTLab 2 platform (Phase 1) and cyclotron updates (Phase 2) from both practical and regulatory perspectives. We summarize our experience manufacturing FDG on the FASTLab 2 module with a high-yielding self-shielded niobium (Nb) fluorine-18 target. Results Following installation of Nb targets for production of fluorine-18, a 55 μA beam for 22 min generated 1330 ± 153 mCi of [18F]fluoride. Using these cyclotron beam parameters in combination with the FASTLab 2, activity yields (AY) of FDG were 957 ± 102 mCi at EOS, corresponding to 72% non-corrected AY (n = 235). Our workflow, inventory management and regulatory compliance have been greatly simplified following the synthesis module and cyclotron upgrades, and patient wait times for FDG PET have been cut in half at our nuclear medicine clinic. Conclusions The combination of FASTlab 2 and self-shielded Nb fluorine-18 targets have improved our yield of FDG, and enabled reliable and repeatable manufacture of the radiotracer for clinical use.https://deepblue.lib.umich.edu/bitstream/2027.42/145727/1/41181_2018_Article_48.pd

Radiochemical syntheses. vol.I, Radiopharmaceuticals for positron emission tomography

xxiii, 343 p. : ill. ; 25 cm

Defra Soil Protection Research in the Context of the Soil Natural Capital / Ecosystem Services Framework

Summary: "A Nation that destroys its soil destroys itself." This quote from, F.D. Roosevelt, 1937, from a letter written to all state Governors in the USA following the dust bowl, encapsulates the importance of soil protection. The dust bowl brought about legislation to protect and conserve soils as a fundamental natural resource in the USA between 1930 and 1936. In current times we are facing unprecedented pressure on land resources from multiple uses here in the UK and across Europe. In response to these increasing pressures Defra has produced soil protection reports and strategies including the report, ‘Safeguarding our Soils: A Strategy for England’ (PB13297). The vision statement of this document reads, ‘By 2030, all England’s soils will be managed sustainably and degradation threats tackled successfully. This will improve the quality of England’s soils and safeguard their ability to provide essential services for future generations.’ Similarly, the Welsh Assembly Government commissioned, ‘The Welsh Soils Action Plan’ (WSAP, 2009) which has a similar goal. These documents set out the pressing issues with regard to soils, their management and protection, and therefore serve as a useful contextual tool for synthesizing past Defra research with regard to current issues. This report synthesises soil protection research commissioned by Defra between 1990 and 2008, to provide the state of current Defra knowledge with regard to soil protection. Contextually, an attempt is made to fit the synthesized knowledge into the Natural Capital / Ecosystem Services framework. It offers a bold, fresh approach that will orient the report firmly in the context of strengthening the linking of science and policy through Natural Capital and Ecosystem Services, and firmly aligns the research with ongoing EU efforts. The report is comprised of 5 work packages for Defra project SP1607 “Defra research on soil protection 1990 - 2008: Synthesis of outputs’. Defra has made a firm commitment to adopt the ecosystems approach which is designed to convey the value of ecosystems, their capital, and their goods and services into the decision making / policy development process. The workpackages address the following: WP1: Chapter 1) Place England and Wales soil policy and research efforts in the wider context of European and International policy. Chapter 2) Identify and synthesize knowledge of needs of farmers, resource managers and the wider society. Chapter 3) Describe the soil natural capital / ecosystem services framework. WP2: Chapter 4) Evaluate current indicators and soil sampling/measurement strategy. Chapter 5) Evaluate work done on the quantification of soil capital. Chapter 6) Evaluate work done on the soil Ecosystem Services. WP3: Chapter 7) Identify Impact of climate change on soils, soil function, and threats to soil protection. Chapter 8) Identify threats to soils, for the England and Wales context; Evaluate research tackling threats that may degrade soil capital or reduce services. WP4: Chapter 9) Evaluate work done on the valuing of soil Natural Capital. WP5: Chapter 10) Future Vision

An updated synthesis of N1′‐([11C]methyl)naltrindole for positron emission tomography imaging of the delta opioid receptor

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/167550/1/jlcr3898.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/167550/2/jlcr3898_am.pd

An updated radiosynthesis of [18F]AV1451 for tau PET imaging

Abstract Background [18F]AV1451 is a commonly used radiotracer for imaging tau deposits in Alzheimer’s disease (AD) and related non-AD tauopathies. Existing radiosyntheses of [18F]AV1451 require complex purifications to provide doses suitable for use in clinical imaging studies. To address this issue, we have modified the synthesis of [18F]AV1451 to use only 0.5 mg precursor, optimized the Boc-deprotection step and developed a simplified method for HPLC purification of the radiotracer. Results An optimized [18F]AV1451 synthesis using a TRACERLab FXFN module led to high radiochemical yield (202 ± 57 mCi per synthesis) and doses with excellent radiochemical purity (98 ± 1%) and good specific activity (2521 ± 623 Ci/mmol). Conclusion An updated and operationally simple synthesis of [18F]AV1451 has been developed that is fully automated and prepares radiotracer doses suitable for use in clinical tau PET studies

An updated synthesis of [11C]carfentanil for positron emission tomography (PET) imaging of the μ‐opioid receptor

[11 C]Carfentanil ([11 C]CFN) is a selective radiotracer for in vivo positron emission tomography imaging studies of the μ-opioid system that, in our laboratories, is synthesized by methylation of the corresponding carboxylate precursor with [11 C]MeOTf, and purified using a C2 solid-phase extraction cartridge. Changes in the commercial availability of common C2 cartridges have necessitated future proofing the synthesis of [11 C]CFN to maintain reliable delivery of the radiotracer for clinical imaging studies. An updated synthesis of [11 C]CFN is reported that replaces a now obsolete purification cartridge with a new commercially available version and also substitutes the organic solvents used in traditional production methods with ethanol

Cyclotron-based production of 68Ga, [68Ga]GaCl3, and [68Ga]Ga-PSMA-11 from a liquid target

Abstract Purpose To optimize the direct production of 68Ga on a cyclotron, via the 68Zn(p,n)68Ga reaction using a liquid cyclotron target. We Investigated the yield of cyclotron-produced 68Ga, extraction of [68Ga]GaCl3 and subsequent [68Ga]Ga-PSMA-11 labeling using an automated synthesis module. Methods Irradiations of a 1.0 M solution of [68Zn]Zn(NO3)2 in dilute (0.2–0.3 M) HNO3 were conducted using GE PETtrace cyclotrons and GE 68Ga liquid targets. The proton beam energy was degraded to a nominal 14.3 MeV to minimize the co-production of 67Ga through the 68Zn(p,2n)67Ga reaction without unduly compromising 68Ga yields. We also evaluated the effects of varying beam times (50–75 min) and beam currents (27–40 μA). Crude 68Ga production was measured. The extraction of [68Ga]GaCl3 was performed using a 2 column solid phase method on the GE FASTlab Developer platform. Extracted [68Ga]GaCl3 was used to label [68Ga]Ga-PSMA-11 that was intended for clinical use. Results The decay corrected yield of 68Ga at EOB was typically > 3.7 GBq (100 mCi) for a 60 min beam, with irradiations of [68Zn]Zn(NO3)2 at 0.3 M HNO3. Target/chemistry performance was more consistent when compared with 0.2 M HNO3. Radionuclidic purity of 68Ga was typically > 99.8% at EOB and met the requirements specified in the European Pharmacopoeia ( 50% (~ 1.85 GBq, 50 mCi); yields improved as processes were optimized. Labeling yields for [68Ga]Ga-PSMA-11 were near quantitative (~ 1.67 GBq, 45 mCi) at EOS. Cyclotron produced [68Ga]Ga-PSMA-11 underwent full quality control, stability and sterility testing, and was implemented for human use at the University of Michigan as an Investigational New Drug through the US FDA and also at the Royal Prince Alfred Hospital (RPA). Conclusion Direct cyclotron irradiation of a liquid target provides clinically relevant quantities of [68Ga]Ga-PSMA-11 and is a viable alternative to traditional 68Ge/68Ga generators.http://deepblue.lib.umich.edu/bitstream/2027.42/174048/1/41181_2020_Article_106.pd